Approximately 5 million Americans suffer from chronic heart failure (CHF) with 550,000 new cases and more than 250,000 deaths annually. In addition, 30-50% of these deaths are sudden and have been attributed to ventricular tachyarrhythmias, bradycardia, and electro-mechanical dissociation. Little is understood about the underlying substrate that supports and maintains the tachyarrhythmia. One possibility for an arrhythmogenic substrate is the fibrotic myocardium that accompanies CHF. The main goal of this proposal is to determine the role of cardiac fibrosis in promoting ventricular tachyarrhythmias. Previous studies have shown that chronic administration of aldosterone and 1% dietary NaCI in rats leads to perivascular and interstitial fibrosis and microscopic scarring of the right and left heart similar to that which appears in CHF. Additionally, spironolactone, an aldosterone receptor antagonist, has proven to reduce mortality in humans with CHF and cardiac fibrosis in the hyperaldosteronism rat model. We will test our hypothesis that hyperaldosteronism-induced cardiac remodeling promotes ventricular tachyarrhythmias in the following treatment groups: aldosterone/salt, aldosterone/salt plus spironolactone, and untreated controls. The specific aims are to (1) determine the relationship between LV hemodynamic function and progression of cardiac fibrosis at one-week intervals for each of the four treatment groups, (2) perform epicardial activation mapping to test for conduction block, changes in conduction velocity, and increased dispersion of activation or refractoriness, and (3) monitor the electrocardiogram (ECG) by telemetry for spontaneous tachyarrhythmias and sudden cardiac death. The electrophysiological measures from these experiments will be correlated with amount and location of cardiac fibrosis. This goal of this research is to demonstrate a specific mechanism(s) whereby hyperaldosteronism- induced cardiac remodeling can cause an increased risk of sudden cardiac death or susceptibility to life threatening cardiac arrhythmias. Should this mechanism(s) be successfully demonstrated, it might be possible to identify the population most at risk, and perhaps protect them. [unreadable] [unreadable] [unreadable]